The neuroendocrine and immune systems control the organism's response to inflammatory stimuli. The neuropeptide CRH is an important mediator of immune responsibeness, both via activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in glucocorticoid secretion from the adrenal gland, as well as via catecholamine release from the sympathetic nervous system. There fore, CRH may suppress the immune response by increasing levels of glucocorticoid and catecholamines. In addition to these effects of centrally released CRH, we have recently shown that CRH secreted in peripheral tissues during immune activation exerts potent proinflammatory effects. I propose to study the role of CRH in the inflammatory process in CRH deficient mice. CRH-deficient (CRH-/-) mice, recently developed in our laboratory by targeted gene inactivation, will be used to test the hypothesis that CRH deficiency alters immune responsiveness either directly or by modulation of glucocorticoid and catecholamine secretion. The effects of CRH and glucocorticoid deficiency on the development of the immune system will be evaluate d. The relative contribution of CRH, glucocorticoid, and catecholamines to immune responsiveness iwll be assessed in three experimental models of inflammation: endotoxemia, acute aseptic inflammation, and autoimmune arthritis. These models will be also used to evaluate the role of gonadal steroids and adrenal glucocorticoid in the sexual dimorphism of the immune response in CRH-/- and wild type mice. The proposed studies will advance the understanding of the pathogenesis of inflammation and autoimmunity, and thus, may provide new insignts for more effective management of autoimmune diseases and endotoxemia.